Cerebral Septic Emboli: A Unique Complication of Clostridium septicum- Induced Myonecrosis

Abstract

Nontraumatic clostridial myonecrosis infections are predominantly caused by Clostridium septicum. Most patients have an underlying gastrointestinal malignancy. This case presents a rare association of spontaneous clostridial myonecrosis preceding cerebral septic emboli with underlying invasive colorectal adenocarcinoma. A 60-year-old male with a history of hypertension, diabetes, and a family history of colon cancer presented to the emergency room with worsening left-sided chest pain radiating to his left shoulder. Extensive workup revealed elevated D-dimer, troponin, C-reactive protein, white blood cell count, and creatinine phosphokinase. Due to his clinical signs, symptoms, elevated white count, and further decompensation, he was started on antibiotics for sepsis. Physical exam revealed left upper extremity (LUE) crepitus consistent with imaging of innumerable soft tissue gas collections along the LUE. Incision, drainage, and myomectomy were performed due to concerns of myositis and necrotizing infection. Muscle biopsy revealed myonecrosis, and subsequent samples were positive for C. septicum. Postoperative pressor support and several sessions of surgical debridement were required. He continued to deteriorate and developed left-sided paralysis. Computed tomography head revealed several white matter infarcts indicative of septic emboli. The patient slowly recovered neurologically after switching to central nervous system-penetrating antibiotics. Months later, a colonoscopy revealed cecal adenocarcinoma. This case features a unique course of spontaneous C. septicum infection. There are high mortality rates, and previous studies report an association with colorectal malignancies. Therefore, preventative and diagnostic evaluations are imperative with a confirmed C. septicum infection. To our knowledge, this is the first case reported of cerebral septic emboli secondary to spontaneous myonecrosis with C. septicum, highlighting a unique burden of emboli-induced neurological deficits.

Introduction

Clostridium septicum is a gram-positive, anaerobic, spore-forming, bacillus bacterium known to cause gas gangrene. Traumatic gas gangrene is usually associated with a form of trauma causing direct inoculation of Clostridium spores to compromised tissue, such as surgery, subcutaneous medication administration, or parenteral injection. ¹ This is most commonly due to the Clostridium perfringens species. Clostridium infections have been connected to farming or trauma, and most cases have other preexisting illnesses, including diabetes, cancer, and/or other immunologic disorders, cytopenia, and immunosuppression.^1,2 Unlike traumatic gas gangrene, nontraumatic, or spontaneous gas gangrene is caused without any visible signs of external wound and is commonly due to C. septicum, as it is more likely to cause infection without associated injury ¹ leading to gas gangrene of the muscle, or spontaneous clostridial myonecrosis.

Spontaneous clostridial myonecrosis is a life-threatening infection leading to rapid destruction of the muscle, which is often fatal without prompt surgical intervention. ³ The clinical manifestations begin with a sudden onset of excruciating pain within 2 to 3 days^1,3 of initial infection, with some cases reporting as soon as 6 hours. ¹ Hypotension, tachycardia, shock, and renal failure often follow with an associated low-grade fever.^1,3 As the infection spreads, local swelling with large serosanguinous-filled bullae develops with surrounding blanching of overlying skin. ³ Toxic delirium, stupor, and unconsciousness follow.^1,3

The main source of C. septicum infections is due to a compromised gastrointestinal tract, often secondary to mucosal perforations, ulcerations, or cancer. ¹ There have been cases previously described with underlying colonic neoplastic malignancy,^4,5 the scrotum, ⁶ arm muscle in association with cecal adenocarcinoma, ⁷ and leukemia. ⁸ In this case, a 60-year-old man with a history of hypertension, uncontrolled diabetes, and a family history of colon cancer, suffered from atraumatic spontaneous clostridial myonecrosis of the left arm due to C. septicum infection after trimming weeds in his garden. Nearly 5 months from the onset of symptoms, the patient was found to have invasive cecal adenocarcinoma.

Case Presentation

A 60-year-old male with a history of hypertension and poorly controlled diabetes presented to the emergency room (ER) with left-sided chest pain radiating to his left shoulder, which worsened since that morning. Of note, he also has a strong family history of colon such that the patient’s mother was diagnosed with colorectal cancer with recurrence three times. Blood pressure was 251/156 mmHg, pulse 138 beats/min, respiratory rate 36 breaths/min, and temperature 99.5°F (37.5°C). Extensive workup in the ER revealed elevated D-dimer, troponin, C-reactive protein, white blood count, and creatine phosphokinase (Table 1). However, an ultrasound of the left upper extremity (LUE) and initial CT angiography of the chest, abdomen, and pelvis revealed no significant findings.

Table 1.

Laboratory Values of Patient on Day of Onset of Symptoms, March 28, 2023.

Lab	Day of symptoms	Reference value
Hematologic
Hemoglobin	16.4	14-18 g/dL
Hematocrit	48.4	42%-50%
White blood cell	17.9	4000-11 000 cell/µL
Platelet	285 000	150 000-450 000 cell/µL
D-dimer	0.75	< 0.5 µg/mL
INR	1.8	0.8-1.1
Troponin	0.06	≤0.04 ng/mL
Metabolic panel
Sodium	139	136-145 mEq/L
Potassium	3.9	3.5-5.0 mEq/L
Bicarbonate	20	23-28 mEq/L
Chloride	107	98-106 mEq/L
Blood urea nitrogen	30	9-20 mg/dL
Creatinine	2.7	0.7-1.3 mg/dL
Alanine aminotransferase	31	10-40 Units/L
Aspartate aminotransferase	25	10-40 Units/L
Lactate dehydrogenase	267	80-225 Units/L
Creatinine phosphokinase	538	55-170 Units/L

Abnormal lab values are indicated in bold. INR, international normalized ratio.

Laboratory test reference ranges in adults (accessed October 27, 2024). All reference ranges are for males.

In the ER, the patient decompensated, requiring intubation. Given his abnormal vital signs, elevated white count, and a source of infection, the patient was started on clindamycin, piperacillin/tazobactam, and linezolid for sepsis. On exam, crepitus was felt along the LUE. Computed tomography (CT) of the chest, LUE, and neck revealed innumerable soft tissue gas collections along the posterior aspect of the LUE (Figure 1).

Figure 1.

CT left upper extremity demonstrating soft tissue gas collections. Innumerable abnormal mildly expansile soft tissue gas collections (yellow circle) extending from the left posterior deltoid into the left triceps muscle compartments along the posterior aspect of the left shoulder and upper extremity. CT, computed tomography.

The patient was taken to the operating room (OR) for incision and drainage due to concerns of left triceps myositis and possible necrotizing infection. Unexpectedly, the muscle was healthy, appearing with patches of ecchymosis. No purulence, necrosis, or visible gas was noted. However, a muscle biopsy was obtained, revealing myonecrosis. Exploration and deep excisional debridement were subsequently performed, removing a 5 × 3 cm segment of tissue. Intraoperative muscle swab was positive for C. septicum (Table 2).

Table 2.

Bacteriology Report From Left Upper Extremity.

Bacteriology test	Results
Specimen	Intraoperative surgical muscle wound, left shoulder
Gram stain	Rare epithelial cells, no organisms seen
Culture results	Small number of Clostridium septicum

Postoperatively, the patient was transferred to the intensive care unit where he required pressor support. In the subsequent days, the patient required several trips to the OR for further debridement of the LUE. During this time, the patient’s status continued to deteriorate, developing rhabdomyolysis and acute kidney injury. Due to the patient’s elevated INR and D-dimer, disseminated intravascular coagulation (DIC) was also considered as a possible cause of this patient’s stroke, as it causes both thrombotic and hemorrhagic characteristics occurring simultaneously. ⁹ However, this was further excluded as a differential diagnosis due to the patients’ lack of thrombocytopenia (leukocyte count 285 000/µL), normal hemoglobin (16.4 g/dL; Table 1), and no signs of active bleeding. However, on day 6 of admission, a head CT was ordered due to the onset of left-sided paralysis, which revealed innumerable white matter infarcts (Figure 2). Magnetic resonance imaging (MRI) of the brain further revealed numerous rounded foci of diffusion restriction scattered in cerebral white matter involving the basal ganglia, cerebral cortex, and right superior cerebellar artery distribution, with evidence of cavitation significant for septic emboli (Figure 3). The patient was comatose and intubated. Further neurological examination revealed no response to painful stimuli or vocal commands, absent oculocephalic reflex with horizontal nystagmus and occasional downward gaze, no motor response or spontaneous movement, corneal reflex intact, and decorticate posture. Ampicillin was added to the patient’s antibiotic regimen for better central nervous system (CNS) penetration. Although the transesophageal echocardiogram (TEE) was initially negative for endocarditis with no vegetations and a normal left ventricular ejection function (LVEF), repeat TEE revealed moderately depressed ventricular systolic function with LVEF of 30% to 50%. During the remainder of his 22-day stay, the patient made a slow neurologic recovery. Nearly 5 months following the onset of his symptoms, the patient underwent a colonoscopy, which revealed a cecal mass consistent with cecal adenocarcinoma (T2 N0). He previously had no history of colonoscopy due to the patient’s refusal of the procedure despite adequate insurance coverage. A right hemicolectomy and loop ileostomy were successfully performed, removing the patient’s colonic mass.

Figure 2.

CT head without contrast demonstrating multiple embolic white matter infarcts mid-sagittal (A) and transverse (B) CT imaging showing patchy bilateral foci of decreased white matter attenuation (yellow arrows). CT, computed tomography.

Figure 3.

Brain MRI. Transverse MRI of brain showing numerous rounded foci of diffusion and cavitation. Appearance suggests a showering pattern of embolic infarcts. MRI, magnetic resonance imaging.

The patient was discharged to a skilled nursing facility with significant neurological deficits but in stable condition. At discharge, the patient was unable to speak, although his wife reported gradual improvement in speech and efforts toward regaining mobility.

Discussion

Hematogenous spread of C. septicum to the CNS has generally been limited to brain abscesses, cerebritis, and meningitis with pneumocephalus as a common secondary complication of the latter.^{10 -12} Even without compromise of the blood-brain barrier, C. septicum can have significant neurological complications, such as ischemic stroke or hemorrhage secondary to sepsis. In Crowley et al, ¹¹ the authors discuss a case of isolated meningeal vasculopathy in the setting of C. septicum bacteremia. Similarly, Martin et al ¹² described C. septicum causing widespread cranial vessel injury without emboli, which resulted in cerebral hemorrhage following septic DIC.

In the case of our 60-year-old male with C. septicum bacteremia, we present a novel presentation of widespread white matter infarcts secondary to septic emboli. There has been a previous case reporting C. septicum infection leading to right-sided focal, neurological deficits, however, this was due to an ischemic stroke in the left middle cerebral artery. ¹³ No other cases illustrating the seeding of septic emboli from C. septicum have been reported.

A similar case study published previously also highlighted a case of C. septicum-induced myonecrosis of the upper extremity, however, of the right arm seen in an 81-year-old female. Similar to our presenting patient, she also had a history of hypertension and diabetes and was overall well and ambulating normally prior to the sudden onset of severe right upper extremity (RUE) pain. Physical examination also revealed crepitus, and an X-ray of RUE marked soft tissue swelling, and the patient was started on doxycycline. Gram-positive rods were identified from one of the bullae, but C. septicum was not definitively determined as the etiological agent at this time. She was taken to the OR for incision and removal. This patient also suddenly decompensated, developing cardio-respiratory arrest requiring intubation. Unfortunately, the patient succumbed shortly after.

In the case by Gazzaniga, ⁷ C. septicum with underlying cecal adenocarcinoma was unfortunately only identified postmortem. It was speculated that the patient succumbed to this infection due to septicemia from shock after ablation, however, no further diagnostic studies, such as TEE, CT, MRI, or further blood work confirming or excluding other diagnoses, were provided. In addition, this case did not note any focal neurological deficits on physical exam or observe cerebral septic emboli, making our case a unique presentation of C. septicum.

Septic emboli are most frequently associated with bacterial endocarditis, septic thrombophlebitis, periodontal wounds, central venous catheter infections, and implants. ¹⁴ Neurologic events secondary to septic emboli are most commonly associated with mitral valve involvement, ¹⁴ and although this patient had reduced LVEF on repeat TEE following left-sided paralysis, there were no evident vegetations.

Mortality rates associated with C. septicum have been reported to be as high as 70%. Studies report that as many as half of all patients with C. septicum have an associated colorectal malignancy. ¹⁵ The pathophysiologic relationship between C. septicum and colon cancer is not comprehensively addressed in the literature. It is known that C. septicum infections are mediated by alpha toxin, in which its hemolytic and lethal effects can induce fatal toxic shock. ¹⁶ In previous literature, it was hypothesized that the alpha toxin has a cytotoxic effect on vascular endothelium, which leads to subsequent fluid loss, myonecrosis, and ultimately, shock. ¹⁶ Due to the scarcity of literature published on the pathophysiology of C. septicum and its association with colorectal malignancy, the exact relationship between the 2 has not been fully elucidated. However, in recent studies, C. septicum alpha toxin has been found to activate nucleotide-binding domain-like receptor P3 (NLRP3) in both mice and humans. ¹⁷ The activation of NLRP3 leads to binding of caspase-1 ¹⁸ to generate the inflammasome, which in turn mediates the activation of inflammatory cytokines interleukin-18 and interleukin-1β. ¹⁹ Chronic inflammation leads to colonic hyperplasia and dysplasia. This chronic inflammation is hypothesized to be responsible for the pathogenic relationship between the bacterium and colorectal malignancy. ¹⁹ Thus, C. septicum’s anaerobic, spore-forming features, alpha toxin lethality, and chronic activation of NLRP3 inflammasome cumulatively contribute to the pathogenic mechanism of colorectal cancer.

This report on spontaneous C. septicum infection presents valuable clinical insights but also has several limitations that should be considered, including, but not limited to: generalizability, causality versus association, and a limited evidence base. First, this is a single study of a 60-year-old male with specific comorbidities of hypertension, poorly controlled diabetes, a family history of colon cancer, and a unique clinical course. Such a specific case may not represent the typical presentation or outcomes of C. septicum infections, limiting the generalizability of findings to broader populations. In addition, the report suggests a potential link between C. septicum infection and colorectal malignancy based on the patient’s subsequent diagnosis of cecal adenocarcinoma. However, it does not establish a clear causal relationship due to the lack of robust evidence or controlled studies demonstrating direct causation. Finally, the exact mechanism linking myonecrosis to septic emboli and subsequent neurological deficits is not fully elucidated. This underscores the need for further research to understand the pathophysiology and management of such complications. While the case report provides valuable clinical observations and insights into a rare presentation of C. septicum infection, it is crucial to interpret its findings within the context of these limitations. Future studies with larger sample sizes, controlled designs, and systematic reviews are needed to further explore the epidemiology, clinical characteristics, optimal management strategies, and potential associations of C. septicum infections with colorectal malignancies.

Conclusion

This case features a unique course of spontaneous C. septicum infection resulting in cerebral septic emboli. Due to the high mortality rates and a strong association with colon cancer, it is imperative that every patient with confirmed C. septicum infection undergo appropriate diagnostic evaluations. This case underscores the importance of preventative screening. The United States Preventive Services Task Force recommends patients be screened for colon cancer between the ages 45 and 75 years. ²⁰ In this case, our 60-year-old patient with a strong maternal family history of colon cancer did not fulfill the necessary routine health screening, which resulted in a sequela of clinical complications. Accordingly, it is imperative to take preventative measures and begin regular screening for colon cancer to reduce possible fatal complications—such as myonecrosis and septic embolic stroke.

Furthermore, to our knowledge, this is the first reported case of septic emboli resulting in white matter infarcts secondary to spontaneous myonecrosis with C. septicum, highlighting a unique burden of emboli-induced neurological deficits.